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Anti-inflammatory and immunomodulatory properties of ?1-antitrypsin without inhibition of elastase.

ABSTRACT: The rationale of ?1-antitrypsin (AAT) augmentation therapy to treat progressive emphysema in AAT-deficient patients is based on inhibition of neutrophil elastase; however, the benefit of this treatment remains unclear. Here we show that clinical grade AAT (with elastase inhibitory activity) and a recombinant form of AAT (rAAT) without anti-elastase activity reduces lung inflammatory responses to LPS in elastase-deficient mice. WT and elastase-deficient mice treated with either native AAT or rAAT exhibited significant reductions in infiltrating neutrophils (23% and 68%), lavage fluid levels of TNF-? (70% and 80%), and the neutrophil chemokine KC (CXCL1) (64% and 90%), respectively. Lung parenchyma TNF-?, DNA damage-inducible transcript 3 and X-box binding protein-1 mRNA levels were reduced in both mouse strains treated with AAT; significantly lower levels of these genes, as well as IL-1? gene expression, were observed in lungs of AAT-deficient patients treated with AAT therapy compared with untreated patients. In vitro, LPS-induced cytokines from WT and elastase-deficient mouse neutrophils, as well as neutrophils of healthy humans, were similarly reduced by AAT or rAAT; human neutrophils adhering to endothelial cells were decreased by 60-80% (P < 0.001) with either AAT or rAAT. In mouse pancreatic islet macrophages, LPS-induced surface expression of MHC II, Toll-like receptor-2 and -4 were markedly lower (80%, P < 0.001) when exposed to either AAT or rAAT. Consistently, in vivo and in vitro, rAAT reduced inflammatory responses at concentrations 40- to 100-fold lower than native plasma-derived AAT. These data provide evidence that the anti-inflammatory and immunomodulatory properties of AAT can be independent of elastase inhibition.

SUBMITTER: Jonigk D

PROVIDER: S-EPMC3773761 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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Anti-inflammatory and immunomodulatory properties of α1-antitrypsin without inhibition of elastase.

Jonigk Danny D Al-Omari Mariam M Maegel Lavinia L Müller Meike M Izykowski Nicole N Hong Jaewoo J Hong Kwangwon K Kim Soo-Hyun SH Dorsch Martina M Mahadeva Ravi R Laenger Florian F Kreipe Hans H Braun Armin A Shahaf Galit G Lewis Eli C EC Welte Tobias T Dinarello Charles A CA Janciauskiene Sabina S

Proceedings of the National Academy of Sciences of the United States of America 20130823 37

The rationale of α1-antitrypsin (AAT) augmentation therapy to treat progressive emphysema in AAT-deficient patients is based on inhibition of neutrophil elastase; however, the benefit of this treatment remains unclear. Here we show that clinical grade AAT (with elastase inhibitory activity) and a recombinant form of AAT (rAAT) without anti-elastase activity reduces lung inflammatory responses to LPS in elastase-deficient mice. WT and elastase-deficient mice treated with either native AAT or rAAT ...[more]

PMID: 23975926

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Dataset Information

Anti-inflammatory and immunomodulatory properties of ?1-antitrypsin without inhibition of elastase.

Publications

Anti-inflammatory and immunomodulatory properties of α1-antitrypsin without inhibition of elastase.

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